Since mucosal immunity is likely to form the first line of defense against sexually acquired HIV-1 specific immunity in this compartment. The innate tropism of Shigella for inductive sites in the organized lymphoid tissue of the colonic mucosal surface, naturally targets attenuated derivatives of this organism to these sites allowing for the exploitation of this property in a HIV-1 vaccine. Further, the ability of Shigella to escape the endosomal compartment and replicate within the cytoplasm of infected cells, suggests that this organism may provide a mechanism for delivery of nucleic acid vaccines to the mucosal immune compartment. In support, these investigators and others have recently reported that genetically-engineered, attenuated Shigella strains are capable of delivering eukaryotic expression cassettes to animal tissue. The central hypothesis of this proposal, therefore, is that live oral Shigella delivery vehicles will provide a specialized mechanism for the delivery of an HIV-1 RNA vaccine to the mucosal immune compartment. The investigators believe that the realization of this strategy will greatly improve both the efficiency and safety of the Shigella nucleic acid vaccine delivery system. Further, the applicants propose to address their hypothesis by developing Shigella HIV-1 env RNA vaccine vectors and to measure their effect in mice. The overall goal of this pilot study, therefore, is to provide a foundation for further development of Shigella RNA vaccine vectors.
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